Bronchiolitis hospital admission in infancy is associated with later preschool ventilation inhomogeneity.

BACKGROUND: Rhinovirus (RV) positive bronchiolitis episodes in infancy confer a higher risk to develop asthma in later childhood with associated lung function impairments. We aimed to investigate the association between the type of virus causing a bronchiolitis hospitalization episode and lung ventilation inhomogeneities at preschool age. METHODS: Infants hospitalized with a clinical diagnosis of moderate (ward admission) or severe (pediatric intensive care ward admission) bronchiolitis were prospectively followed-up at preschool age to assess nitrogen (N2 ) multiple breath washout (MBW). Lung clearance index (LCI), functional residual capacity (FRC), and concentration normalized phase III slope analysis (SnIII ) indices were reported from ≥2 technically acceptable trials. Differences between groups were calculated using logistic and linear regression and adjusted for confounders (sex, age at bronchiolitis admission, height at visit, maternal asthma, and doctor-diagnosed asthma, including interaction terms between the latter three). An interaction term was included in a regression model to test for an interaction between RV bronchiolitis severity and MBW parameters at preschool age. RESULTS: One hundred and thirty-nine subjects attended preschool follow-up, of which 84 out of 103 (82%) performing MBW had technically acceptable data. Children with a history of RV positive bronchiolitis (n = 39) had increased LCI (adjusted ß-coefficient [aß] = 0.33, 95% confidence interval [CI] 0.02-0.65, p = 0.040) and conductive airways ventilation inhomogeneity [Scond ] (aß = 0.016, CI 0.004-0.028, p = 0.011) when compared with those with a RV negative bronchiolitis history (n = 45). In addition, we found a statistical interaction between RV bronchiolitis and bronchiolitis severity strengthening the association with LCI (aß = 0.93, CI 0.20-1.58, p = 0.006). CONCLUSION: Children with a history of hospital admission for RV positive bronchiolitis in infancy might be at a higher risk of lung ventilation inhomogeneities at preschool age, arising from the peripheral conducting airways.

The association of exhaled nitric oxide with air pollutants in young infants of asthmatic mothers.

BACKGROUND: Exhaled nitric oxide is a marker of airway inflammation. Air pollution induces airway inflammation and oxidative stress. Little is known about the impact of air pollution on exhaled nitric oxide in young infants. METHODS: The Breathing for Life Trial recruited pregnant women with asthma into a randomised controlled trial comparing usual clinical care versus inflammometry-guided asthma management in pregnancy. Four hundred fifty-seven infants from the Breathing for Life Trial birth cohort were assessed at six weeks of age. Exhaled nitric oxide was measured in unsedated, sleeping infants. Its association with local mean 24-h and mean seven-day concentrations of ozone, nitric oxide, nitrogen dioxide, carbon monoxide, sulfur dioxide, ammonia, particulate matter less than 10 µm (PM10) and less than 2.5 µm (PM2.5) in diameter was investigated. The air pollutant data were sourced from local monitoring sites of the New South Wales Air Quality Monitoring Network. The association was assessed using a 'least absolute shrinkage and selection operator' (LASSO) approach, multivariable regression and Spearman's rank correlation. RESULTS: A seasonal variation was evident with higher median exhaled nitric oxide levels (13.6 ppb) in warmer months and lower median exhaled nitric oxide levels (11.0 ppb) in cooler months, P = 0.008. LASSO identified positive associations for exhaled nitric oxide with 24-h mean ammonia, seven-day mean ammonia, seven-day mean PM10, seven-day mean PM2.5, and seven-day mean ozone; and negative associations for eNO with seven-day mean carbon monoxide, 24-h mean nitric oxide and 24-h mean sulfur dioxide, with an R-square of 0.25 for the penalized coefficients. These coefficients selected by LASSO (and confounders) were entered in multivariable regression. The achieved R-square was 0.27. CONCLUSION: In this cohort of young infants of asthmatic mothers, exhaled nitric oxide showed seasonal variation and an association with local air pollution concentrations.

Polymorphisms in Glutathione S-Transferase (GST) Genes Modify the Effect of Exposure to Maternal Smoking Metabolites in Pregnancy and Offspring DNA Methylation.

Maternal smoking in pregnancy (MSP) affects the offspring's DNA methylation (DNAm). There is a lack of knowledge regarding individual differences in susceptibility to exposure to MSP. Glutathione S-transferase (GST) genes are involved in protection against harmful oxidants such as those found in cigarette smoke. This study aimed to test whether polymorphisms in GST genes influence the effect of MSP on offspring DNAm. Using data from the Isle of Wight birth cohort, we assessed the association of MSP and offspring DNAm in 493 mother-child dyads (251 male, 242 female) with the effect-modifying role of GST gene polymorphism (at rs506008, rs574344, rs12736389, rs3768490, rs1537234, and rs1695). MSP was assessed by levels of nicotine and its downstream metabolites (cotinine, norcotinine, and hydroxycotinine) in maternal sera. In males, associations of hydroxycotinine with DNAm at cg18473733, cg25949550, cg11647108, and cg01952185 and norcotinine with DNAm at cg09935388 were modified by GST gene polymorphisms (p-values < 0.05). In females, associations of hydroxycotinine with DNAm at cg12160087 and norcotinine with DNAm at cg18473733 were modified by GST gene polymorphisms (p-values < 0.05). Our study emphasizes the role of genetic polymorphism in GST genes in DNAm's susceptibility to MSP.

Offspring epigenetic markers at birth related to gestational BMI predict offspring BMI-trajectories from infancy to 26 years.

Objective: To date, epigenetic studies identified differential DNA methylation (DNAm) related to gestational-body mass index (BMI) in offspring at birth. This study investigated whether the identified DNAm in offspring were also associated with BMI trajectories from infancy to age 26 years. Methods: Data of 794 participants from Isle of Wight birth cohort in UK were investigated to study association between BMI trajectories and DNAm related to gestational-BMI at birth. Multinominal logistic regression models were applied to test the association between 1090 DNAm sites reported in three prior epigenome-wide association studies and BMI trajectories. Results: DNAm site cg23089913 (NANOS1) and cg13217064 (SOX14) were associated with early persistent obesity (EPO) and delayed overweight (DOW) trajectories respectively. A higher methylation of cg23089913 showed low odds of being in EPO trajectory (OR: 0.84; 95% CI: 0.76-0.93) while higher methylation of cg13217064 resulted in 1.4-times the odds of being in DOW trajectory when compared to the normal trajectory [Correction added on 22 February 2023, after first online publication: Range of the DNAm site cg23089913 has been changed from 'lower' to 'higher' in the preceding sentence.]. In a gender-stratified analysis, the odds of developing into DOW was 1.8 times in female participants for cg13217064 while not such association was observed in males. Conclusions: Deviations in methylation of cg23089913 (NANOS1) and cg13217064 (SOX14) in newborns may change the risk of having excess body weight.

Fucoxanthin levels in maternal serum at birth and eczema risk in offspring in early childhood: A birth cohort study.

BACKGROUND: Fucoxanthin, a marine xanthophyll carotenoid, has been shown to exert beneficial health effects. Cell-based and animal-based experimental studies have shown that fucoxanthin has the potential to mitigate eczema symptoms. Hence, we sought to assess whether fucoxanthinol 3-arachidate, a fucoxanthin metabolite, measured in maternal serum at birth is associated with eczema development during early childhood. METHODS: Data from the 1989/1990 Isle of Wight birth cohort were analyzed. We focused on data obtained from the 1, 2, and 4 years follow-ups. Fucoxanthinol 3-arachidate was measured in maternal serum at the child's birth as abundance relative to the reference lipids. Eczema was ascertained according to parent-reported clinical history and characteristic morphology and distribution. Log-binomial regression models were used to estimate adjusted risk ratios (aRR) and their 95% confidence intervals (CI). RESULTS: A total of 592 subjects (49.2% males and 50.8% females) were included in the current analysis. Associations between fucoxanthinol 3-arachidate levels and eczema risk during the first 4 years of life (longitudinal analysis) were evaluated using four modeling approaches, which showed higher fucoxanthinol 3-arachidate levels were associated with reduced eczema risk: (i) aRRper 10 unit increase = 0.88, 95% CI: 0.76-1.03; (ii) aRR>0 vs. =0 = 0.67, 0.45-0.99; (iii) aRR≥2.3 vs. <2.3 = 0.66, 0.44-0.98; and (iv) aRRtertile 3 vs. tertile 1 = 0.65, 0.42-0.99. CONCLUSION: Our findings suggest that increased fucoxanthinol 3-arachidate levels measured in maternal serum at the child's birth is associated with reduced eczema risk during the first 4 years of the offspring life.

Association of Metabolites, Nutrients, and Toxins in Maternal and Cord Serum with Asthma, IgE, SPT, FeNO, and Lung Function in Offspring.

The role of metabolites, nutrients, and toxins (MNTs) in sera at the end of pregnancy and of their association with offspring respiratory and allergic disorders is underexplored. Untargeted approaches detecting a variety of compounds, known and unknown, are limited. In this cohort study, we first aimed at discovering associations of MNTs in grandmaternal (F0) serum with asthma, immunoglobulin E, skin prick tests, exhaled nitric oxide, and lung function parameters in their parental (F1) offspring. Second, for replication, we tested the identified associations of MNTs with disorders in their grandchildren (F2-offspring) based on F2 cord serum. The statistical analyses were sex-stratified. Using liquid chromatography/high-resolution mass spectrometry in F0, we detected signals for 2286 negative-ion lipids, 59 positive-ion lipids, and 6331 polar MNTs. Nine MNTs (one unknown MNT) discovered in F0-F1 and replicated in F2 showed higher risks of respiratory/allergic outcomes. Twelve MNTs (four unknowns) constituted a potential protection in F1 and F2. We recognized MNTs not yet considered candidates for respiratory/allergic outcomes: a phthalate plasticizer, an antihistamine, a bile acid metabolite, tryptophan metabolites, a hemiterpenoid glycoside, triacylglycerols, hypoxanthine, and polyphenol syringic acid. The findings suggest that MNTs are aspirants for clinical trials to prevent adverse respiratory/allergic outcomes.

Sex and obesity status modify the association between vitamin D and eczema among adolescents.

BACKGROUND: Epidemiologic studies have reported inconsistent associations between vitamin D and eczema. This study sought to assess whether sex and obesity status could modify the association between vitamin D and eczema. METHODS: A cross-sectional study enrolled 763 adolescents in Kuwait. 25-hydroxyvitamin D (25(OH)D) was measured in venous blood. Current eczema was defined according to clinical history and characteristic morphology and distribution. RESULTS: In sex-stratified analysis, decreased 25(OH)D levels were associated with increased current eczema prevalence among males (adjusted odds ratio (aOR)tertile 1 vs. tertile 3: 2.14, 95% confidence intervals (CI): 1.07-4.56), but not among females (aORtertile 1 vs. tertile 3: 1.08, 95% CI: 0.71-1.66). Further stratification by obesity status showed that lower 25(OH)D levels were associated with increased current eczema prevalence among overweight/obese males (per 10-unit decrease in 25(OH)D levels: aOR: 1.70, 95% CI: 1.17-2.46). Such an association was weaker and statistically non-significant among overweight/obese females (per 10-unit decrease in 25(OH)D levels: aOR: 1.26, 95% CI: 0.93-1.70). CONCLUSIONS: Sex and obesity status modified the association between vitamin D levels and eczema, with an inverse association observed among overweight/obese males, but not among overweight/obese females. These results suggest that preventive and clinical management strategies could vary by sex and obesity status. IMPACT: The current study showed that sex and obesity modify the association between vitamin D and eczema among adolescents. An inverse association between vitamin D and eczema was observed among overweight/obese males, but this association was not as pronounced among overweight/obese females. Vitamin D was not associated with eczema among underweight/normal weight males and females. The identification of effect modification by sex and obesity status add to the current scientific knowledge and further highlight the complexity of the association between vitamin D and eczema. These results may promote a more individualized approach to the future prevention and clinical management of eczema.

Sex differences in the intergenerational link between maternal and neonatal whole blood DNA methylation: a genome-wide analysis in 2 birth cohorts.

BACKGROUND: The mother-child inheritance of DNA methylation (DNAm) variations could contribute to the inheritance of disease susceptibility across generations. However, no study has investigated patterns of mother-child associations in DNAm at the genome-wide scale. It remains unknown whether there are sex differences in mother-child DNAm associations. RESULTS: Using genome-wide DNAm profiling data (721,331 DNAm sites, including 704,552 on autosomes and 16,779 on the X chromosome) of 396 mother-newborn pairs (54.5% male) from the Boston Birth Cohort, we found significant sex differences in mother-newborn correlations in genome-wide DNAm patterns (Spearman's rho = 0.91-0.98; p = 4.0 × 10-8), with female newborns having stronger correlations. Sex differences in correlations were attenuated but remained significant after excluding X-chromosomal DNAm sites (Spearman's rho = 0.91-0.98; p = 0.035). Moreover, 89,267 DNAm sites (12.4% of all analyzed, including 88,051 [12.5% of analyzed] autosomal and 1,216 [7.2% of analyzed] X-chromosomal sites) showed significant mother-newborn associations in methylation levels, and the top autosomal DNAm sites had high heritability than the genome-wide background (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.92). Additionally, significant interactions between newborn sex and methylation levels were observed for 11 X-chromosomal and 4 autosomal DNAm sites that were mapped to genes that have been associated with sex-specific disease/traits or early development (e.g., EFHC2, NXY, ADCYAP1R1, and BMP4). Finally, 18,769 DNAm sites (14,482 [77.2%] on the X chromosome) showed mother-newborn differences in methylation levels that were significantly associated with newborn sex, and the top autosomal DNAm sites had relatively small heritability (e.g., the top 100 autosomal DNAm sites had a medium h2 of 0.23). These DNAm sites were mapped to 2,532 autosomal genes and 978 X-chromosomal genes with significant enrichment in pathways involved in neurodegenerative and psychological diseases, development, neurophysiological process, immune response, and sex-specific cancers. Replication analysis in the Isle of Wight birth cohort yielded consistent results. CONCLUSION: In two independent birth cohorts, we demonstrated strong mother-newborn correlations in whole blood DNAm on both autosomes and ChrX, and such correlations vary substantially by sex. Future studies are needed to examine to what extent our findings contribute to developmental origins of pediatric and adult diseases with well-observed sex differences.

Eczema among adolescents in Kuwait: Prevalence, severity, sleep disturbance, antihistamine use, and risk factors.

Background: Eczema (atopic dermatitis) is a common inflammatory skin disease that is more prevalent in children and adolescents than adults. In Kuwait, there is a lack of empirical knowledge on eczema epidemiology among adolescents. Therefore, this study aimed to estimate the prevalence of eczema symptoms and severity, assess the frequency of eczema-related nocturnal sleep disturbance and its relation to antihistamine use, and determine factors that are associated with eczema prevalence and eczema-related nocturnal sleep disturbance. Methods: A school-based cross-sectional study enrolled adolescents (n = 3864) aged 11-14 years across Kuwait. Information on eczema symptoms and clinical history, use of antihistamines, parental history of eczema, mode of delivery, and childhood life-style factors and exposures were reported by parents. Current eczema was defined as chronic or chronically relapsing itchy dermatitis with characteristic morphology and distribution in the past 12 months. Among subjects reporting current itchy rash, frequency of nocturnal sleep disturbance due to itchy rash in the past 12 months was reported as: never, <1 night per week, and ≥1 nights per week. Associations were assessed by applying a modified Poisson regression to estimate adjusted prevalence ratios (aPR) and 95% confidence intervals (CI). Results: The prevalence estimate of current (past 12 months) itchy rash was 20.5% (735/3593) and current eczema was 10.2% (388/3791), with 19.5% (736/3775) reporting history of ever doctor-diagnosed eczema. Among subjects with current itchy rash, nocturnal sleep disturbance due to itchy rash affected 21.7% (157/724) of participants for <1 night per week and affected 12.7% (92/724) of participants for ≥1 nights per week. Antihistamine use at least once per month increased as the frequency of nocturnal sleep disturbance due to itchy rash increased (Ptrend <0.001). Factors that demonstrated association with current eczema prevalence included underweight body mass index (aPR = 1.71, 95% CI: 1.16-2.53), Cesarean section delivery (1.29, 1.01-1.65), and maternal (1.72, 1.35-2.19) and paternal (1.83, 1.44-2.32) history of eczema. Frequent (≥1 nights per week) nocturnal sleep disturbance was associated with Cesarean section delivery (1.98, 1.37-2.85), exposure to household tobacco smoke (1.70, 1.18-2.47), and dog-keeping (1.93, 1.06-3.52). Conclusions: Eczema symptoms are common among adolescents in Kuwait, with similar epidemiological patterns as those observed in western countries. A large proportion of affected adolescents reported nocturnal sleep disturbance due to itchy rash. Modifiable risk factors were associated increased prevalence of eczema and night awakenings.

Sex Differences in the Association of Sibship Size and Position in Sibship with Lipid Profile during Adolescence: A Cross-Sectional Study.

Background: Epidemiologic studies have reported associations of sibship size and position of the child in the sibship with multiple health outcomes, including adiposity and diabetes. However, little is known about sibling effects on lipids. Hence, this study sought to evaluate associations of the number of total, older, and younger siblings with lipid profile among adolescents. Methods: In a cross-sectional study among high school students aged 14 to 19 years, lipid levels were measured in capillary blood. Parents reported the number of siblings (total, older, and younger). Geometric means of lipids were calculated, and linear regression was used to estimate the ratio of geometric means (RoGM) and 95% confidence intervals (CI). Analyses were sex stratified. Results: Of the total study sample (n = 1,584), 758 (47.9%) were boys and 826 (52.1%) were girls, with median age of 16.0 years. Total cholesterol (TC) was lower by 8% (adjusted-RoGM = 0.92, 95% CI: 0.88-0.96) among boys with ≥3 older siblings compared to those with no older siblings. Similarly, boys with ≥3 younger sibling compared to those with no younger siblings had reduced TC by 7% (adjusted-RoGM = 0.93, 0.87-0.99). Moreover, an increased number of total siblings (≥4 vs. 0/1: adjusted-RoGM = 0.80, 0.67-97) and older siblings (≥3 vs. 0: adjusted-RoGM = 0.90, 0.82-0.98) were associated with reduced low-density lipoprotein cholesterol (LDL-C) among boys. Similarly, lower levels of triglycerides (TG) were seen among boys with ≥3 older siblings compared to those with no older siblings (adjusted-RoGM = 0.87, 0.78-0.96). A higher number of younger siblings was associated with increased high-density lipoprotein cholesterol (HDL-C) among boys (≥3 vs. 0: adjusted-RoGM = 1.08, 1.01-1.17). Sibship characteristics were not associated with lipids among girls. Conclusions: Increased number of total, older, and younger siblings were associated with favorable lipid profiles among adolescent boys, but not girls. Mechanisms underlying these associations need further investigations.

Association of childhood BMI trajectory with post-adolescent and adult lung function is mediated by pre-adolescent DNA methylation.

BACKGROUND: Body mass index (BMI) has been shown to be associated with lung function. Recent findings showed that DNA methylation (DNAm) variation is likely to be a consequence of changes in BMI. However, whether DNAm mediates the association of BMI with lung function is unknown. We examined the mediating role of DNAm on the association of pre-adolescent BMI trajectories with post-adolescent and adulthood lung function (forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC). METHODS: Analyses were undertaken in the Isle of Wight birth cohort (IOWBC). Group-based trajectory modelling was applied to infer latent BMI trajectories from age 1 to 10 years. An R package, ttscreening, was applied to identify CpGs at 10 years potentially associated with BMI trajectories for each sex. Linear regressions were implemented to further screen CpGs for their association with lung function at 18 years. Path analysis, stratified by sex, was applied to each screened CpG to assess its role of mediation. Internal validation was applied to further examine the mediation consistency of the detected CpGs based on lung function at 26 years. Mendelian randomization (MR-base) was used to test possible causal effects of the identified CpGs. RESULTS: Two BMI trajectories (high vs. low) were identified. Of the 442,475 CpG sites, 18 CpGs in males and 33 in females passed screening. Eight CpGs in males and 16 CpGs in females (none overlapping) were identified as mediators. For subjects with high BMI trajectory, high DNAm at all CpGs in males were associated with decreased lung function, while 8 CpGs in females were associated with increased lung function at 18 years. At 26 years, 6 CpGs in males and 14 CpGs in females showed the same direction of indirect effects as those at 18 years. DNAm at CpGs cg19088553 (GRIK2) and cg00612625 (HPSE2) showed a potential causal effect on FEV1. CONCLUSIONS: The effects of BMI trajectory in early childhood on post-adolescence lung function were likely to be mediated by pre-adolescence DNAm in both males and females, but such mediation effects were likely to diminish over time.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

Association of prenatal acetaminophen use and acetaminophen metabolites with DNA methylation of newborns: analysis of two consecutive generations of the Isle of Wight birth cohort.

Acetaminophen is used by nearly two-thirds of pregnant women. Although considered safe, studies have demonstrated associations between prenatal acetaminophen use and adverse health outcomes in offspring. Since DNA methylation (DNAm) at birth may act as an early indicator of later health, assessments on whether DNAm of newborns is associated with gestational acetaminophen use or its metabolites are needed. Using data from three consecutive generations of the Isle of Wight cohort (F0-grandmothers, F1-mothers, and F2-offspring) we investigated associations between acetaminophen metabolites in F0 serum at delivery with epigenome-wide DNAm in F1 (Guthrie cards) and between acetaminophen use of F1 and F2-cord-serum levels with F2 cord blood DNAm. In epigenome-wide screening, we eliminated non-informative DNAm sites followed by linear regression of informative sites. Based on repeated pregnancies, indication bias analyses tested whether acetaminophen indicated maternal diseases or has a risk in its own right. Considering that individuals with similar intake process acetaminophen differently, metabolites were clustered to distinguish metabolic exposures. Finally, metabolite clusters from F1-maternal and F2-cord sera were tested for their associations with newborn DNAm (F1 and F2). Twenty-one differential DNAm sites in cord blood were associated with reported maternal acetaminophen intake in the F2 generation. For 11 of these cytosine-phosphate-guanine (CpG) sites, an indication bias was excluded and five were replicated in F2 with metabolite clusters. In addition, metabolite clusters showed associations with 25 CpGs in the F0-F1 discovery analysis, of which five CpGs were replicated in the F2-generation. Our results suggest that prenatal acetaminophen use, measured as metabolites, may influence DNAm in newborns.

Does DNA methylation mediate the association of age at puberty with forced vital capacity or forced expiratory volume in 1 s?

BACKGROUND: Age of pubertal onset is associated with lung function in adulthood. However, the underlying role of epigenetics as a mediator of this association remains unknown. METHODS: DNA methylation (DNAm) in peripheral blood was measured at age 18 years in the Isle of Wight birth cohort (IOWBC) along with data on age of pubertal events, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) at 26 years. Structural equation models were applied to examine mediation effects of DNAm on the association of age at pubertal events with FVC and FEV1. Findings were further tested in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. RESULTS: In the IOWBC, for females, 21 cytosine-phosphate-guanine sites (CpGs) were shown to mediate the association of age at puberty with FVC or FEV1 at 26 years (p<0.05). In males, DNAm at 20 CpGs was found to mediate the association of age at puberty with FVC (p<0.05). At almost all these CpGs, indirect effects (effects of age at pubertal events on FVC or FEV1 via DNAm) contributed a smaller portion to the total effects compared to direct effects (e.g. at cg08680129, ∼22% of the estimated total effect of age at menarche on FVC at age 26 was contributed by an indirect effect). Among the IOWBC-discovered CpGs available in ALSPAC, none of them was replicated in ALSPAC (p>0.05). CONCLUSIONS: Our findings suggest that post-adolescence DNAm in peripheral blood is likely not to mediate the association of age at pubertal onset with young adulthood FVC or FEV1.

DNA Methylation and Asthma Acquisition during Adolescence and Post-Adolescence, an Epigenome-Wide Longitudinal Study.

The role of epigenetics in the pathogenesis of asthma acquisition in adolescence and post-adolescence has been unknown. We carried out a longitudinal epigenome-wide association study, using data from the Isle of Wight Birth Cohort (IOWBC). To improve statistical power, we first screened CpGs based on associations of DNA methylation (DNAm) at an age of 10 years (pre-adolescence) with asthma acquisition at 10-18 years (during adolescence). A logistic regression with repeated measures was applied to CpGs that passed screening to examine the associations of pre-adolescence DNAm with asthma acquisition from 10-18 years and 18-26 years, with an interaction term to evaluate transition period specificity. Findings were further tested in an independent birth cohort, ALSPAC. In total, 205 CpGs (with 150 being females) showed associations with asthma acquisition (main or interaction effects) at FDR = 0.05 in IOWBC, of which 112 (90 being females) showed consistent associations in the ALSPAC. Genes that the identified CpGs were mapped to, e.g., AKAP1 and ENO1, have been shown to be associated with the risk of asthma. Our findings indicated that DNAm at specific CpGs was associated with asthma acquisition. CpGs showing such associations were likely to be different between males and females and, at certain CpGs, were unique to a specific transition period.

Newborn DNA methylation and asthma acquisition across adolescence and early adulthood.

BACKGROUND: Little is known about the association of newborn DNA methylation (DNAm) with asthma acquisition across adolescence and early adult life. OBJECTIVE: We aim to identify epigenetic biomarkers in newborns for asthma acquisition during adolescence or young adulthood. METHODS: The Isle of Wight Birth Cohort (IOWBC) (n = 1456) data at ages 10, 18 and 26 years were assessed. To screen cytosine-phosphate-guanine site (CpGs) potentially associated with asthma acquisition, at the genome scale, we examined differentially methylated regions (DMR) using dmrff R package and individual CpG sites using linear regression on such associations. For CpGs that passed screening, we examined their enrichment in biological pathways using their mapping genes and tested their associations with asthma acquisitions using logistic regressions. Findings in IOWBC were tested in an independent cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. RESULTS: In total, 2636 unique CpGs passed screening, based on which we identified one biological pathway linked to asthma acquisition during adolescence in females (FDR adjusted p-value = .003 in IOWBC). Via logistic regressions, for females, four CpGs were shown to be associated with asthma acquisition during adolescence, and another four CpGs with asthma acquisition in young adulthood (FDR adjusted p-value < .05 in IOWBC) and these eight CpGs were replicated in ALSPAC (all p-values < .05). DNAm at all the identified CpGs was shown to be temporally consistent, and at six of the CpGs was associated with expressions of adjacent or mapping genes in females (all p-values < .05). For males, 622 CpGs were identified in IOWBC (FDR = 0.01), but these were not tested in ALSPAC due to small sample sizes. CONCLUSION AND CLINICAL RELEVANCE: Eight CpGs on LHX5, IL22RA2, SOX11, CBX4, ACPT, CFAP46, MUC4, and ATP1B2 genes have the potential to serve as candidate epigenetic biomarkers in newborns for asthma acquisition in females during adolescence or young adulthood.

Having Children Is Associated with a Higher Prevalence of COVID-19 among Young Adults in Kuwait.

OBJECTIVES: The role of children in the transmission of coronavirus disease 2019 (COVID-19) remains unclear. We investigated whether having children is associated with self-reported COVID-19 among adults. SUBJECTS AND METHODS: A web-based cross-sectional study enrolled adults living in Kuwait (n = 2,355; aged ≥21 years). Prior COVID-19 diagnosis and having children were self-reported. Associations were assessed using Poisson regression, and adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Of the 2,355 participants (1,595 female subjects), 744 (31.6%) and 605 (25.7%) were of age 21-29 and 30-39 years, respectively. Overall, 4.8% (114/2,355) of the participants reported having had COVID-19, with 4.8% of females and 5.1% of males reporting prior COVID-19 diagnosis. In the total study sample, having children showed a trend for association with having had COVID-19 (aPR: 1.46, 95% CI: 0.99-2.14, p = 0.056). Among participants aged 21-29 years, having children was associated with an increased prevalence of COVID-19 (aPR: 2.50, 95% CI: 1.21-5.20, p = 0.014). Such an association was not detected in adults aged ≥30 years. CONCLUSIONS: Our epidemiological findings highlight the possible role of children in spreading COVID-19. Hence, preventive measures should consider the role of children.

Sex-specific developmental trajectories of eczema from infancy to age 26 years: A birth cohort study.

BACKGROUND: Eczema is a common inflammatory skin disease with varying developmental trajectories/patterns that are influenced by different risk factors. The aim of this study was to investigate eczema development from infancy to early adulthood by identifying distinct developmental trajectories that describe disease patterns over time and evaluate the role of prenatal and early-life risk factors. METHODS: The Isle of Wight Birth Cohort (n = 1456) was prospectively assessed at birth, 1, 2, 4, 10, 18 and 26 years. In all assessments, eczema was defined as chronic or chronically relapsing itchy dermatitis lasting >6 weeks with characteristic morphology and distribution in the past 12 months. Developmental trajectories of eczema between 1 or 2 and 26 years were identified separately for males and females by applying semiparametric mixture models. Associations were assessed by applying a modified Poisson regression to estimate adjusted risk ratios (aRR) and 95% confidence intervals (CI). RESULTS: In both males and females, the following eczema developmental trajectories were identified: unaffected/transient (males: 77.7% vs. females: 73.0%), mid-onset late-resolving (males: 7.8% vs. females: 4.4%), late-onset (males: 5.2% vs. females: 9.5%) and early-onset persistent (males: 9.3% vs. females: 5.4%). In females, an additional trajectory was identified as follows: early-onset early-resolving (7.7%). Among males, filaggrin gene (FLG) variants (aRR = 2.45, 95% CI: 1.34-4.46) and paternal eczema (2.66, 1.39-5.08) were associated with the early-onset persistent trajectory. Among females, maternal eczema (2.84, 1.42-5.70) and high birthweight (2.25, 1.08-4.69) were associated with the early-onset persistent trajectory. CONCLUSIONS: Four and five trajectories represented eczema development among males and females, respectively, with different predisposing risk factors. Our results indicate that males and females may experience a different course of eczema.